Reported 5-FU-induced cardiac side effects may be explained by drug-induced hemodynamic changes and/or by direct myocardial toxicity due to regional drug uptake. This question was studied in 11 animals given constant infusions and 6 animals given bolus 5-FU infusions into the hepatic artery. Six animals, which received normal saline infusion, served as controls. A second aim was to study possible pulmonary drug clearance. Aortic, pulmonary arterial, and coronary sinus plasma 5-FU concentrations were determined during constant and after the bolus infusions of 5-FU. The V5 ECG, aortic, pulmonary arterial, and right atrial pressures were recorded continuously, and cardiac output and coronary sinus blood flow were recorded intermittently in all animals. No significant alterations in hemodynamic variables were seen during constant infusion. After the bolus infusion, an increased arterio-mixed venous oxygen content difference was recorded. Pharmacokinetic data after 3-min infusions indicated pulmonary drug uptake and release; during constant infusions, the data indicated myocardial drug uptake. As there were no alterations in myocardial oxygen demand or supply or in systemic hemodynamics during this myocardial drug uptake, it is likely that the cardiotoxicity is related to the direct effects of the drug on cardiac myocytes.